1. Genetics and Primary Care
What’s New in Prenatal
Genetic Screening

2. Genetics in Medicine: the 21st Century
The Human Genome Project has brought inherited health factors to the forefront
Genetic risk assessment, screening and testing is becoming part of primary medical care
Clinical genetics and primary care need to work together to offer appropriate services
The Human Genome Project, completed on April 14, 2003,
With collaboration from genetics specialists, genetic risk assessment, screening and testing can become an important part of primary medical care

3. We Are Working Together
Risk assessment for common genetic conditions
likely to be performed in the primary care/prenatal setting
Screening and testing for genetic conditions
increasingly performed in primary care/prenatal care
Patients with rare or more complex genetic conditions, risks, or family histories
likely continue to be served by genetics specialists
Consultation with genetics specialists is critical as the field is advancing at a rapid pace and genetic tests and interpretation of results are complex.

4. Outline Preconception/prenatal genetic risk assessment and screening
Family/personal history questionnaire
Ethnicity-based screening
Maternal serum screening and ultrasound
How, When, Where to refer patients
Resource Information

5. Family History Questionnaire
Screens for reproductive genetic risks
Appropriate for patients considering pregnancy or already pregnant
Contains referral guidelines for genetic services
See Sample Family History Questionnaire in resource packet
Use for patients considering pregnancy or already pregnant
Screens for patients who may have reproductive genetic risks.
Not comprehensive – captures only genetic and maternal health information relevant to current/future offspring

6. Assessment Areas Maternal age Family medical history (both sides)
Current pregnancy/pre-pregnancy history
Ethnic background (both sides)

7. Maternal Age
Maternal age 35 or older at time of delivery: increased risk for chromosome abnormalities
Options for prenatal testing/screening:
CVS
Amniocentesis
Multiple marker screening
1st or 2nd trimester, or combined
Ultrasound

8. Family Medical History
For a family history of a diagnosed genetic condition or birth defect and a patient who is currently pregnant, referral to a Prenatal Diagnosis Clinic is appropriate.
Examples:
Nephew with Duchenne Muscular Dystrophy
Brother with Fragile X syndrome
Previous child with spina bifida, etc.

9. Family Medical History
For a non-specific, but concerning history, referral to a Medical Genetics Clinic (e.g. OHSU) is appropriate.
Examples:
Close family member with mental retardation, etiology unknown
Multiple family members with ‘kidney disease’
Previous child with seizure disorder and developmental delay

10. Pregnancy History
During pregnancy, any reported exposures or maternal conditions would be reasonable to refer to a genetics service – especially those known to be teratogens
E.g. accutane, seizure medications, lithium, coumadin, “street drugs”, high fevers, viral infections, maternal diabetes, etc.
Preconception counseling should always include a discussion of folic acid
Thought to decrease the risk of neural tube defects by 50-70%
0.4 mg is recommend for all women
4.0 mg is recommended for women at increased risk

11. Ethnicity-Based Genetic Carrier Screening
Purpose: To detect couples at risk for prenatally diagnosable genetic diseases
Tests offered based on ethnic background
Should be offered to patients:
Seeking preconception counseling, OR
Seeking infertility care, OR
During the first or early second trimester of pregnancy

12. Carrier Frequencies based on Ethnic Origin
Population
Condition
Carrier Frequency
African-American
Sickle Cell
Cystic Fibrosis
Beta-Thalassemia
1 in 10
1 in 65
1 in 75
Ashkenazi Jewish
Gaucher disease
Tay-Sachs disease
Dysautonomia
Canavan disease
1 in 15
1 in 26 – 1 in 29
1 in 30
1 in 32
1 in 40
Asian
Alpha-Thalassemia
1 in 20
1 in 50
European American
1 in in 29
French Canadian, Cajun
Tay Sachs disease
Hispanic
1 in 46
1 in in 50
Mediterranean
1 in 25
1 in 29

13. Principles of Carrier Screening
Counseling before screening should include:
Purpose, voluntary nature of screening
Range of symptoms and severity of each disease
Risk of carrier status and affected offspring
Meaning of positive and negative results
Factors to consider in decision-making
Further testing would be necessary for prenatal diagnosis
Appropriate carrier tests should be offered to each patient based on his/her ethnic background & family history
Counseling before screening should include:
Purpose of screening, voluntary nature of testing
Range of symptoms and severity of each disease being screened for
Risk of carrier status and affected offspring based on ethnicity
Meaning of positive and negative results
Factors to consider in deciding to have or not have testing

14. Informed Consent Utilize patient resources materials
Patient brochures about CF and other ethnicity-based genetic screening available from multiple sources
Carrier screening videos can be shown in office settings
Document informed consent discussion and patient decision

15. Important Points Carrier screening is optional
Patient education/informed decision-making is crucial
Testing can be done sequentially or concurrently
If >12 weeks gestation, discuss concurrent testing
Insurance coverage for carrier screening???
Varies by insurer (not covered by OHP and some other major insurers)
Genetic counseling is available to carriers and strongly advised for carrier/carrier couples
Genetic counseling is available prior to testing should a couple want to discuss each of these disorders in more depth before making decisions about testing.

16. Caucasian Patients: ACOG guidelines, Oct. 2001
Offer cystic fibrosis carrier screening to:
Individuals with a family history of CF
Reproductive partners of carriers/persons with CF
Couples where one or both partners are Caucasian & are planning a pregnancy or seeking prenatal care
“Make CF screening available” to couples in other racial or ethnic groups at lower risk
ACOG guidelines, Oct recommend pffeing CF screening to:
Persons with a family history of CF
Reproductive partners of carriers or persons with CF
Couples in whom one or both partners are Caucasian and are planning a pregnancy or seeking prenatal care AND
“Making CF screening available” to couples in other racial or ethnic groups at lower risk

17. CF Carrier Screening
1/25 to 1/29 carrier rate in general Caucasian population and Ashkenazi Jewish population
Carrier screening by DNA mutation analysis
ACOG suggests panel of 25 most common mutations
Some labs do additional mutations but at higher cost
Mutations differ in severity – contact genetics to discuss particular carrier results

18. Carrier Rates: Cystic Fibrosis
Ethnic Group
Carrier Frequency
Detection Rate
Carrier risk after negative test
Northern European Caucasian
1/25 – 1/29
85-90%
~1 in 250
Ashkenazi Jewish
1/26 - 1/29
97%
~1 in 930
Southern European Caucasian
1/29
70-80%
~1 in 97 to 1 in 140
Hispanic
1/46
57%
~1 in 105
African American
1/65
72%
~1 in 232
Asian
~1/90 (?)
~30% (?)
Not available

19. Asian Patients Standard to review MCV
If <80, screen for thalassemia w/quantitative hemoglobin electrophoresis
Alpha-thalassemia carrier rates up to 1/20
Beta-thalassemia carrier rates 1/30 to 1/50
Cystic fibrosis carrier rate 1/90 or less
Detection rate is very low (~ 30%)
Not standard to do CF screening
Make available upon patient request

20. Hispanic/Latino Patients
No standard protocol for carrier testing
Cystic Fibrosis: carrier rate 1/46
Beta-thalassemia: carrier rate 1/30 to 1/50
Sickle cell or other hemoglobin trait: Carrier rate 1/30 (Caribbean) to 1/200
Could review MCV as a general screen

21. African-American Patients
Standard to offer Sickle Cell screening
Sickle cell carrier rate is 1/10 to 1/12
Use Hb electrophoresis (NOT sickle dex)
Standard to review MCV
Beta-thalassemia carrier rate about 1/75
If MCV low, offer thalassemia screen w/quantitative Hb electrophoresis
CF carrier rate 1/65
no standards re: offering CF carrier screening

22. Ashkenazi Jewish Patients
Standard of care to offer carrier screening for:
Tay-Sachs disease
Cystic Fibrosis
Canavan disease
Familial Dysautonomia
All autosomal recessive conditions
Carrier testing for other disorders also available (high anxiety/family history?)
Standard of care to offer to persons of AJ background or their partners prior to conception or during 1st trimester:
Tay-Sachs disease
Cystic Fibrosis
Canavan disease

23. Maternal Serum Screening
Tests maternal serum markers to detect increased risk of fetal trisomy 21, trisomy 18 and/or neural tube defects
2nd trimester maternal serum screening
1st trimester maternal serum screening (with or without nuchal translucency measurement)
Integrated maternal serum screening
Other variations combining 1st and 2nd trimester screening results

24. Maternal Serum Screening
Patient education points:
‘This is only a screening test’
‘The test is optional’
‘A negative result does not guarantee a healthy baby’
‘A positive result does not mean that the baby has a problem, BUT further testing (ultrasound & CVS or amniocentesis) would be offered’
Offered to all patients regardless of age – ‘there is a small risk in every pregnancy for these conditions’

25. 2nd Trimester Serum Screening
Timing: 15 to 20 weeks gestation
Choices:
Triple screen
Quad screen
Cost ~$200
Insurance coverage varies
Triple covered by most, Quad by some

26. Triple Screen Analytes used (with maternal age):
Alpha-fetoprotein (AFP)
Unconjugated estriol (uE3)
Beta-Human Chorionic Gonadotropin (b-HCG)
Detection rates/screen-positive rates vary by lab
Detection rates with a 5% screen-positive rate
Down syndrome: 60-70%
Trisomy 18: 60%
NTD: 75-80%

27. Quad Screen Analytes used (with maternal age):
adds dimeric inhibin-A (DIA) to AFP, uE3 and beta-HCG
Detection rates with 5% screen positive rate
Down syndrome: 75-80%
Trisomy 18: 60%
NTD: 75-80%
Use quad screen over triple when available and when covered by insurance

28. 2nd Trimester screening tips
Use ultrasound dating if available
Even when LMP still used for due date
U/S dating gives more accurate results
Cons of 2nd trimester screening
Later gestation - limits prenatal diagnosis options
Not as accurate for multiple gestation
Some labs do not offer calculations for twin gestations
Pros:
Includes screening for NTDs via AFP analysis
Often covered by insurance

29. 1st Trimester Maternal Serum Screening
Timing:
24-84 mm CRL (9 to 13+6 weeks gestation)
Analytes used (with maternal age):
free Beta HCG
PAPP-A
Detection rates with 5% screen positive rate:
Down syndrome: 68%
Trisomy 18: 90%
Costs:
$ for serum
$200 plus for NT U/S

30. 1st Tri Serum + NT
Serum results combined with nuchal translucency (NT) measurement *
*Measured by an NT-certified ultrasonographer
Best visualized at CRL = 45 – 84 mm (11-14 wks gestation)
Increased NT = increased risk for Down syndrome / other disorders
Detection rates with 5% screen positive rate:
Down syndrome – 90%,
Trisomy 18 – >90%
*ACOG Committee Opinion Obstet Gynecol 2004 Jul;104(1):215-7

31. Increased NT
Increased NT measurement (>3.5mm) associated with increased risk for:
Chromosome abnormalities
Major structural cardiac defects
NTDs, other structural anomalies, and specific genetic syndromes
SAB, IUFA, SGA and stillbirth
If normal chromosomes and >NT, can offer:
2nd trimester MSAFP screen
Fetal anomaly scan between weeks
fetal echocardiogram between weeks

32. Pros: 1st Trimester Serum + NT screen
Fingerstick dried blood sample easy to collect and send via prepaid FedEx envelope
Draw blood <11 wks if possible (more sensitive)
Results take about 1 week
Results available at earlier gestation
Allows choice of CVS or amnio
Higher detection rate than 2nd trimester screen
More accurate for multiple gestations
Separate ultrasound/NT results on each fetus

33. Cons: 1st Trimester Serum + NT screen
Requires NT measurement performed at a certified center
Often only available at perinatal centers
Often necessitates patient travel
Does not screen for NTDs
Need to discuss 2nd trimester AFP screening with patients who have had 1st trimester screening
May not be covered by insurance

34. Integrated Serum Testing
Combined 1st and 2nd trimester biochemical screening
1st trimester dried blood sample
2nd trimester venipuncture
Increased detection rate; decreased false positive rate
Combined results given in 2nd trimester after 2nd screen
Good for:
Communities without NT capabilities and/or CVS
Patients who are not highly anxious
Patients who cannot afford 1st trimester US/NT screening

35. Ultrasound/Sonogram Nuchal translucency (NT) and nasal bone (NB)
Accompanies 1st trimester serum screening for Down sy.
Performed by NT and NB certified sonographers
Fetal anatomy – weeks
Offered for significant family history of detectable structural defects or genetic syndrome(s), for f/u of positive serum screens, for prenatal history of known teratogens, etc.
Fetal echocardiogram weeks
Often useful for significant family history of structural cardiac lesions, certain genetic syndromes, certain teratogen exposures,
Not perfect - a normal ultrasound does not mean a healthy baby

36. Fetal Ultrasound/Sonogram
Nuchal translucency (NT) and nasal bone (NB)
Accompanies 1st trimester serum screening for Down syndrome.
Performed by NT- and NB-certified sonographers
Fetal anatomy – weeks
Offered for significant family history of detectable structural defects or genetic syndrome(s), for f/u of positive serum screens, for prenatal history of known teratogens, etc.

37. Fetal Ultrasound/Sonogram
Fetal echocardiogram weeks
Often useful for significant family history of structural cardiac lesions, certain genetic syndromes, certain teratogen exposures,
Patient counseling:
Fetal ultrasound is not perfect - a normal ultrasound does not mean a healthy baby

38. Ultrasound/Sonogram

39. Who to Refer – Ethnic Background
Individuals with a family history of cystic fibrosis or other autosomal recessive disease
Couples where both members are known carriers for an autosomal recessive disease
Couples where one member is a carrier and has additional questions
Pregnant carriers who do not have results on the father of baby

40. Who To Refer – Positive Family History
If patient or partner indicates family history of birth defects, inherited condition(s) or history of pregnancy exposure:
Assess level of concern and desire for more information about risks to pregnancy
Refer for genetic counseling with patient consent

41. Who To Refer – Prenatal Genetic Services
Advanced maternal age
Request for 1st trimester marker screening with NT
Abnormal serum marker screening results
Fetal abnormalities on prenatal ultrasound
Personal or family history of a known or suspected genetic disorder, birth defect, or chromosome abnormality
Family history of mental retardation of unknown etiology
Patient with a medical condition known or suspected to affect fetal development

42. Who to refer (cont) Exposure to a known or suspected teratogen
Either parent or family member with a chromosome rearrangement
Parent a known carrier or has a family history of a disorder for which prenatal testing is available
Unexplained infertility or multiple pregnancy losses or previous stillbirths
Absence of the vas deferens
Premature ovarian failure

43. Oregon Genetics Providers
Portland
Oregon Health & Science University
Legacy Health Care
Northwest Perinatal Services
Kaiser-Permanente
Eugene
Center for Genetics & Maternal Fetal Medicine
Bend
Genetic Counseling of Central Oregon (cancer only)

44. How, When, Where How? Give a center a call When? ASAP
Where? Oregon Genetics Clinics Contact List

45. Resource Information Provider and patient education materials
Family history questionnaire and assessment guide
Genetic Web Site Reference List
Patient brochures and fact sheets
- list of labs offering carrier testing for specific genetic disorders